PEG has been known as one of the most representative hydrophilic polymers, including natural polymers and synthetic polymers, forming hydrogen bond with water molecule.
PEG is soluble in various organic solvents and exhibits almost no toxicity in human. PEG presents a fully extended structure form in water, so that it can be used to reduce toxicity of medicinal molecules and protect the administered composition from being destroyed by immune system based on the structured steric hinderance by conjugation with other medicinal factors (protein, peptide, enzyme, gene, etc). Thus, PEG can be applied to various medicines to extend their half-lives in human plasma.
It is one advantage of PEG to be able to be conjugated with a medicine which is especially difficult to be applied to human because of its toxicity and insolubility even though highly effective, in order to enhance the solubility of the PEG conjugated drug (PEG-Drug) and reduce it's toxicity.
The mPEG with high purity (>99%) can be obtained by the following two methods.
The classical and general method of preparing mPEG is to react ethylene oxide with methanol in the presence of alkaline earth metal catalysts (Na, K, etc).
U.S. Pat. No. 6,455,639 B1 describes the synthesis of mPEG with at least 99% purity. According to the description, the way to prepare mPEG with high purity is to minimize the moisture included in the reactor and methanol before the polymerization and to minimize sub-reaction possibly caused during the reaction. However, such problems have not been solved therein that a huge amount of organic solvent (such as toluene) is required to eliminate the moisture and re-treatment is impossible when the byproduct (PEG) of the sub-reaction or the level of PDI increases.
Another way to prepare mPEG with high purity is to perform polymerization of mPEG and then separate and purify the included PEG therefrom. Selisko and Ehwald presented that mPEG has been separated and purified with high purity by using gel permeation chromatography (GPC) (Barbara Selisko and Rudolf Ehwald, Journal of Chromatography, 641(1993) 71˜79). This method, however, is only available when the distribution of molecular weight is significantly different between mPEG and PEG, suggesting that this method is difficult to be commercialized.
U.S. Pat. No. 5,298,410 describes that mPEG-succinate is first synthesized and then mPEG with high purity is separated and purified in the presence of methylenechloride by using Dowex50*8-100H resin. However, mPEG-succinate used in the description comprises ester bond which is highly sensitive to water, so that disintegration might be caused during the separation. A requirement of a huge amount of organic solvent is another problem to be commercialized.